Periodontal diseases result in loss of supporting tissues including bone, cementum, and periodontal ligament (PDL), ultimately leading to tooth loss if left untreated. Growth factors have been shown to stimulate bone and soft tissue repair when delivered to periodontal bone lesions. However, human trials have failed to demonstrate clinically successful regeneration. The mode of delivery of osteogenic growth factors appears to be critical for tissue engineering of alveolar bone defects. The long-term goal of this research is to develop optimal reconstructive modalities for the treatment of periodontal diseases. We propose a novel biomimetic/tissue engineering approach. In this approach an unique nano-fibrous polymer scaffolding (mimicking collagen architecture), modified with surface apatite (mimicking bone mineral), and containing microspheres for delivery of bioactive factors (mimicking development and reparative signaling cascades) will be used in periodontal osseous defects to: promote activities of cells at the healing site, e.g., osteoblasts, cementoblasts, and PDL fibroblasts (and their progenitor cells); allow for nutrients, metabolites, and signal molecules to permeate; and guide cell proliferation, differentiation and tissue neogenesis in three dimensions. The specific aims are: 1. To test whether polymer scaffolds with nano-fibrous pore walls are superior to scaffolds with "solid" pore walls, and whether bone mineral-mimic apatite promotes calcified tissue formation, in vitro. 2. To develop a combined nano-fibrous scaffold/biodegradable microsphere delivery system that allows for controlled release and improve bioavailability of putative periodontal regenerative factors and to evaluate their regenerative function, in vitro. 3. To confirm that the microsphere/scaffold systems selected based on the results from studies under aims 1 and 2, provide a superior environment for regeneration of periodontal tissues, in vivo. By accomplishing these specific aims, our understanding of design principles to use for developing an "ideal" modality for restoring tissues destroyed by periodontal diseases will be significantly advanced, resulting in new and improved periodontal regenerative therapies. Furthermore, with our ability to manipulate the scaffolding structure and control the rate and types of factors delivered, this system offers potential for factor, gene and cell delivery approaches for multiple tissue engineering applications.